The Wnt-5a-derived hexapeptide Foxy-5 inhibits breast cancer metastasis in vivo by targeting cell motility.
OBJECTIVE
An inherent problem in breast cancer treatment is that current therapeutic approaches fail to specifically target the dissemination of breast cancer cells from the primary tumor. Clinical findings show that the loss of Wnt-5a protein expression in the primary breast tumor predicts a faster tumor spread, and in vitro analyses reveal that it does so by inhibiting tumor cell migration. Therefore, we hypothesized that the reconstitution of Wnt-5a signaling could be a novel therapeutic strategy to inhibit breast cancer metastasis.


METHODS
We used in vitro techniques to show that 4T1 mouse breast cancer cells responded to the reconstitution of Wnt-5a signaling using our novel Wnt-5a mimicking hexapeptide, Foxy-5, in the same way as human breast cancer cells. Therefore, we could subsequently study its effect in vivo on the metastatic spread of cancer following the inoculation of 4T1 cells into mice.


RESULTS
In vitro analyses revealed that both recombinant Wnt-5a and the Wnt-5a-derived Foxy-5 peptide impaired migration and invasion without affecting apoptosis or proliferation of 4T1 breast cancer cells. The in vivo experiments show that i.p. injections of Foxy-5 inhibited metastasis of inoculated 4T1 breast cancer cells from the mammary fat pad to the lungs and liver by 70% to 90%.


CONCLUSIONS
These data provide proof of principle that the reconstitution of Wnt-5a signaling in breast cancer cells is a novel approach to impair breast tumor metastasis by targeting cell motility. In combination with existing therapies, this approach represents a potential novel therapeutic strategy for the treatment of breast cancer patients.
Säfholm
Annette
A
Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, Sweden.
Tuomela
Johanna
J
Rosenkvist
Jeanette
J
Dejmek
Janna
J
Härkönen
Pirkko
P
Andersson
Tommy
T
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D008113:Liver Neoplasms / Q000378:metabolism / Q000556:secondary / Q000628:therapy*; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use*; D011518:Proto-Oncogene Proteins / Q000276:immunology* / Q000378:metabolism; D051153:Wnt Proteins / Q000276:immunology* / Q000378:metabolism; D000071818:Wnt-5a Protein
D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein